There is growing evidence that the oxidative modification of low density lipoprotein (LDL) may be involved in the pathogenesis of atherosclerosis. Because the cytotoxic aldehyde, 4-hydroxynonenal (HNE), is produced in the oxidation of polyunsaturated fatty acids, experiments were carried out to determine if HNE is produced during the metal ion catalyzed oxidation of LDL, and if so, whether HNE can modify amino acid residues in LDL. When LDL was treated with HNE, both histidine-HNE and lysine-HNE adducts were formed. Oxidation of LDL led to a substantial loss of histidine and lysine residues, and coincidentally to the formation of HNE-histidine and HNE-lysine adducts. These results provide direct evidence that the oxidation of LDL leads to HNE modification of histidine and lysine residues, and serve notice that such modifications may be involved in the pathogenesis of atherosclerosis.